High-throughput screening (HTS) of small-molecule libraries and Natural product extracts is a crucial component of modern-day drug discovery. Popular HTS methods rely largely on fluorescence and FRETbased sensing protocols, which are fraught with inherent limitafions, which include high cost and incompatibility with certain species. Given that an overwhelming majority of drugs candidates are identified through HTS efforts, the long-term goal of this research program is the development of better sensing methods that can quickly identify lead therapeufics under physiologically relevant condifions. The objective of this subproject is the establishment of powerful new platforms and methods that can detect biomolecule binding phenomena. These systems will help map new biological signaling pathways, and identify smallmolecule chemical probes and therapeufic leads. Based on our inifial work and expertise in this area, we have identified the following specific aims for this program: (1) Development of ECL-based Electrode Microarrays for Therapeufic Lead Discovery; and (2) Development of ECL-based Electrode Microarrays for Label-Free Biomolecule Detecfion and Protein Panning. Both ofthese endeavors are innovative as they will permit protein binding interacfions to be probed under a broad array of condifions, using compounds that are often incompafible with modern HTS methods. The proposed research is significant because it will establish new sensing paradigms for protein binding phenomena, provide general and robust platforms to screen small-molecule antagonists, and enable protein-panning experiments to be pursued. Further, by funcfioning as an essenfial cog within a collaborative network, this subproject will not only help define new protein targets for therapeufic development, but also provide the means to identify hit compounds that can be advanced into new chemical probes.